Early-Stage Preclinical Validation of Carbon Monoxide Prodrugs for Acute Kidney Injury - In response to PAR-19-294 (Early-Stage Preclinical Validation of Therapeutic Leads for Diseases of Interest to the NIDDK), we propose to conduct preclinical validation of carbon monoxide (CO) as a therapeutic agent for treating acute kidney injury (AKI), which afflicts a large number of patients with serious and sometimes fatal consequences. Currently, there are no treatment options available other than maintenance therapy. Therefore, developing disease modifying treatment for AKI will address an important, unmet medical need. The proposed work of developing CO-based therapeutics is based on CO’s endogenous signaling roles, the availability of a large amount of literature evidence to show CO’s cyto- and organ-protective effects, our unique chemistry work to pack “CO in a pill” through innovative prodrug design for easy delivery through pharmaceutically acceptable forms, and our own extensive preliminary results in demonstrating the organ-protective effects of such CO prodrugs in animal models of kidney ischemia reperfusion injury and rhabdomyolysis injuries, liver injury, systemic inflammation, and GI inflammation such as the colon and stomach, among others. In this application, we propose to examine some key preclinical validation issues and aim to produce one or more lead compounds ready for IND-enabling work by the end of the grant period. A very important aspect is our plan to use multiple animal models including the examination in large animals such as pig to conduct the pharmacological assessment, which should give enhanced chance of success when translating into human. Specifically, we propose to pursue the following specific aims (1) design, synthesis, and assessment of CO prodrugs, (2) therapeutic validation of CO prodrug efficacy in mouse models of AKI, and (3) therapeutic validation of CO prodrugs in pig models of AKI. The proposed work will bridge the gap between our long-term goal of developing CO-based therapeutics and the need for preclinical assessments. Upon completion of the project, we will have developed and fully validated the efficacy of a series of innovative CO prodrugs that can either deliver CO systemically or selectively target the kidney and allow for renal enrichment. Further, we will also have developed a pipeline for backup candidates. Collectively, the proposed work will be a major step in developing CO-based therapeutics against AKI and other forms of organ injury.
